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Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1

Isabel Aznarez1, Tomoki T Nomakuchi1, Jaclyn Tetenbaum-Novatt1

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Cell Reports
|May 17, 2018
PubMed

Insights

The splicing factor SRSF1 aids nonsense-mediated mRNA decay (NMD) by increasing UPF1 binding to mRNAs. This reveals a new link between splicing and mRNA quality control, impacting gene expression and disease.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Gene Regulation

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial RNA surveillance pathway.
  • Premature termination codons (PTCs) trigger NMD, degrading aberrant mRNAs.
  • SRSF1 is a known splicing factor with emerging roles in RNA regulation.

Purpose of the Study:

  • To investigate the role of SRSF1 in promoting NMD.
  • To elucidate the mechanism by which SRSF1 influences NMD.
  • To understand the interplay between splicing and NMD.

Main Methods:

  • Analysis of SRSF1's interaction with UPF1 and mRNA.
  • Investigating SRSF1's effect on NMD in the presence of PTCs.
  • Assessing the impact of splicing and EJC deposition on SRSF1-mediated NMD.

Main Results:

  • Transcript-bound SRSF1 enhances UPF1 binding to mRNA in the nucleus, promoting NMD.
  • SRSF1's NMD-promoting activity is dependent on its position downstream of a PTC.
  • Splicing and exon junction complex (EJC) deposition potentiate SRSF1's role in NMD.
  • SRSF1 enhances NMD of endogenous PTC-containing transcripts.

Conclusions:

  • SRSF1 provides an alternative mechanism for UPF1 recruitment, linking splicing and NMD.
  • SRSF1 regulates mRNA fate from splicing to decay, with implications for gene expression and disease.
  • This study uncovers a novel function of SRSF1 in RNA quality control.
Keywords:
EJCNMDRNA splicingSRSF1UPF1

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